This proposal has three major goals. First, we will characterize further the mutations which result in reduced expression of Beta globin genes. Through sequence analysis of Beta-thalassemia alleles associated with different polymorphism haplotypes in various ethnic groups, we expect to discover about 13 new mutations which lead to reduced Beta gene expression. These data, along with those derived from "normal" Beta genes, will greatly expand our knowledge concerning which mutations are detrimental to gene expression and which are tolerated. By 1985 one should be able to present a map of the Beta gene with 30-40 nucleotide positions outside of exons marked for two types of mutations: 1) those that are found in "normal alleles," and 2) those that lead to recuced gene expression. As a corollary to this first objective, we hope to demonstrate that recurrent mutation is at least partially responsible for the high frequency attained by certain mutant alleles in various human populations. Second, we will test the hypothesis that meiotic recombination preferentially occurs within specific DNA sequences in man. We have previously observed two clusters of norandomly associated sequences in the Beta gene region. Randomization of these sequence clusters appears to take place in the DNA region 5' to the Beta gene. Thus, our studies will focus on this region as a potential site for "recombination sequence(s)." Third, we will study the variability of normal Beta globin genes in various populations and construct a phylogenetic tree of human populations. In these latter studies, we aim to contribute to the "molecularization" of population genetics.